There is a fundamental gap in understanding the neural bases for childhood developmental stuttering, particularly with respect to why certain children recover naturally whereas others continue to stutter throughout life and why there is a greater probability of recovery among girls than boys. The long-term goal in this research is to identify neural markers for stuttering and to develop interventions that lead to behavioral and neurophysiological normalization in speech. The overall objective in this application is to identify structural and functional neural markers of stuttering close to symptom onset and determine gender-specific brain developmental trajectory markers that serve to differentiate those children who do or do not recover from stuttering. The central hypothesis is that both boys and girls with persistent stuttering have weaker structural and functional connectivity in brain regions interconnected by the left superior longitudinal fasciculus encompassing ventral premotor and precentral motor areas. Children who recover from stuttering are expected to exhibit developmental brain trajectories that become increasingly similar to controls with increasing age. On the other hand, children who continue to stutter are expected to exhibit less normalization, but a compensatory connectivity in the right hemisphere. The rationale that underlies the proposed research is that an improved understanding of the complex neural phenotypes in stuttering may ultimately lead to identification of neural targets for developing therapeutic interventions. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge to reduce the burdens of illness and disability. Guided by strong preliminary data, the central hypotheses will be tested by pursuing two specific aims: 1) Determine brain structural and functional correlates of early childhood stuttering; and 2) Determine gender-specific neural markers that characterize stuttering persistence. For both aims, already established methods in diffusion tensor imaging and functional connectivity analyses will be used to acquire objective brain data, which will be taken longitudinally from boys and girls beginning as close as possible to stuttering onset. The proposed work is potentially innovative, as it will be the first series of studies designed specifically to identify the sexual dimorphism and the neural bases of risk and persistence of developmental stuttering during early childhood. The results will be significant, because they will provide novel information on the correlation of brain development and gender with stuttering persistence versus recovery. Such results will have an important positive impact, as they will provide markers for early diagnosis and guide future research in identifying specific neural targets for therapy that may differ for boys versus girls who stutter. PUBLIC HEALTH RELEVANCE: The proposed studies address an important and under-investigated area of childhood developmental stuttering that frequently lead to a chronic manifestation in many more males than females. The results from this research are expected to have an important positive impact, as they will help in the identification of gender-specific neural markers that correlate with persistent stuttering. This may, in turn, guide clinical practices in terms of prioritizing intervention and testing of specific neural targets for treatment.